1. Technical Field
This invention relates to a method, apparatus and composition for selectively controlling the temperature of all or a portion of a patient""s body by lowering, maintaining or raising the temperature of a body fluid or tissue to affect the temperature of all or part of the patient""s body, while reducing shivering that typically accompanies such temperature control. More particularly, the invention relates to a heat exchange device in combination with an anti-shivering mechanism to control the temperature of all of a portion of a patient""s body while reducing shivering. The invention also relates to novel compositions that are useful for reducing shivering.
2. Background
The xe2x80x9cset point temperaturexe2x80x9d is the temperature that the body attempts to maintain through the thermoregulatory responses. Under ordinary circumstances, thermoregulatory mechanisms within the human body which include sweating and vasodilation to enhance heat loss, arterio venous (xe2x80x9cAVxe2x80x9d) shunting and vasoconstriction to enhance retaining heat, and shivering to enhance increased generation of body heat, serve to maintain the body at a near constant set point temperature of about 37xc2x0 C. (98.6xc2x0 F.), often referred to as xe2x80x9cnormothermicxe2x80x9d. However, sometimes the body sets a different set point temperature, for example a patient with a fever has an elevated set point temperature, and these mechanisms can serve to maintain an elevated temperature. In the case of a fever, the set point temperature can be higher than normothermic.
There is a temperature slightly below the set point temperature where the body senses that the body temperature is too low and begins to shiver. This temperature is sometimes referred to as the shivering threshold. As with the set point temperature, the shivering threshold is not an absolute temperature but varies between individuals and within the same individual depending on his or her condition.
As a result of the thermoregulatory mechanisms, any heat lost to the environment is precisely balanced by heat produced within the body. Accordingly, attempts to control the body temperature below the set point temperature often produce shivering in the patient, as this is the main method of generating additional metabolic heat. Shivering can increase heat production by 200-500% and thus presents a serious obstacle when attempts are made to reduce a patient""s body temperature.
The thermoregulatory mechanisms provide a formidable defense when attempts are made to lower the body temperature below the set point temperature, for example, when one attempts to induce an artificially low body temperature (a condition known as hypothermia) by lowering the normothermic 37xc2x0 C. to a lower temperature state or when one attempts to maintain normothermia by lowering an elevated body temperature to normothermic 37xc2x0 C. Since there are numerous therapeutic reasons for both inducing hypothermia or inducing normothermia in a patient suffering from an elevated temperature, the thermoregulatory mechanisms must be taken into consideration when designing a therapeutic regimen for controlling the temperature of all or a portion of a patient""s body. Indeed, when the patient has a set point temperature that is above normothermic, for example when the patient has a fever, the shivering threshold may actually be above normothermic as well, and thus even an attempt to maintain a patient""s temperature to normothermia may result in shivering. In addition, even when the thermoregulatory mechanisms have been overcome, the body temperature may continue to drop, possibly below the desired threshold. This xe2x80x9covershootingxe2x80x9d phenomenon can lead to complications. Accordingly, any therapeutic regimen for controlling body temperature preferably does so at a carefully monitored and controlled rate.
It has also been found that in rewarming a patient, either after therapeutic hypothermia or a patient suffering from accidental hypothermia, a very gradual and controlled rewarming rate is desirable. The dramatic generation of metabolic heat due to shivering, particularly in addition to heat added by other means, can result in rapid and uncontrolled rewarming. Therefore therapeutic rewarming at a carefully monitored and controlled rate also requires control over shivering.
Hypothermia may be induced to minimize damage to the brain when a patient has suffered a head injury or stroke, or to minimize damage to heart and brain tissue when a patient has undergone cardiac arrest. It may sometimes also be desirable to induce hypothermia during surgery, especially neurosurgery, once again to minimize tissue damage.
Early techniques involved application of cold to the skin surface or cooling the inspired air, alone or in combination with a compound to inhibit the thermoregulatory center such as chlorpromazine (Ripstein, et al., Surgery (35)1:98-103 (1954)). More recently, in situ blood temperature modification using a heat exchange catheter was described in Ginsburg, U.S. Pat. No. 5,486,208 and Ginsburg, WP 98/268831, the disclosures of which are incorporated herein by reference. This in situ procedure lowers the body temperature much faster and maintains the temperature at that lower level more precisely than the cooled skin surface or cooled breathing air methods described above.
There are also drugs which are capable of assisting in lowering body temperature. However, many require toxic doses in order to achieve the desired hypothermic state. Temperature lowering was also allegedly achieved with chlorpromazine, when administered in combination with a refrigeration blanket (Ripstein, et al, supra), and when administered alone (Chai, et al., Br. J. Pharmac. 57:43-49 (1976)). However, in both these instances, temperature variation after the chlorpromazine was administered was achieved by external cooling or exposure alone and without any significant control of the degree or rate of body cooling. More recently, hypothermia was allegedly induced in rats with a combination of a xcexa opioid receptor agonist and a dopamine receptor blocker or agonist (Adler, et al., U.S. Pat. No. 4,758,562). It has been shown that the xcex12-adrenoreceptor agonists dexmedetomidine and clonidine are able to lower the shivering threshold (Talke, et al., Anesthesiology 87(4):835-841, 1997). In this study, patients at a normal temperature were warmed until sweating then cooled until shivering occurred, as the xcex12-adrenoreceptor agonist was administered. Evaluation of the ability of these agonists and a novel agonist to reduce core temperature were later described in Millan, et al., The Journal of Pharmacology and Experimental Therapeutics 295(3):1192-1205, 2000. However, in both these studies, as with chlorpromazine, temperature variation after the xcex12-adrenoreceptor agonist was administered was achieved with only minor control of the degree or rate of body cooling.
However, in spite of these advances, there continues to be a need to develop a method of safely and temporarily inactivating the shivering response while inducing hypothermia or otherwise reducing the body""s temperature below its set point temperature for an extended period of time, or while gently and slowly raising the body""s temperature from a hypothermic state.
The present invention pertains to a method for controlling the temperature of all or a portion of a patient""s body to a temperature below its set point temperature, while reducing shivering, comprising the steps of: (a) sensing the temperature of all or a portion of the patient""s body; (b) generating a signal based upon the sensed temperature; (c) controlling the temperature of all or a portion of the patient""s body based upon the signal; and (d) administering an agent selected from the group consisting of xcex12-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug to the patient.
In many ways, the muscular activity of shivering, which is a high frequency, random-like muscular contraction that is not coordinated to produce intentional motion, is similar to the high frequency, random-like muscular activity exhibited during some seizures, particularly tonic-clonic seizures. The anticonvulsant medications that act to inhibit the seizures also may act to inhibit the shivering of a patient which is cooled below the shivering threshold. There may also be a more generalized pharmacological inhibition of the thermoregulatory response of the patient which is helpful when the patient""s temperature is controlled by an endovascular cooling system as described below and not by the natural thermoregulatory mechanisms of the body.
The anticonvulsant drugs includes any of the pharmaceutically acceptable anticonvulsant medications including without limitation currently known anticonvulsant drugs which may be useable in accordance with this invention include but are not limited to hydantoins (e.g., phenytoin (Dilantin)), anticonvulsant barbiturates (e.g., phenobarbital), deoxybarbiturates (e.g., primidone), iminostilbenes (e.g., carbamazepine (Tegretol)), succinimides (e.g.,ethosuximide, methsuximide, phensuximide), oxazolidinediones (e.g., trimethadione, paramethadione), benzodiazepines (e.g., diazepam, chlordiazeppoxide, oxazepam, chlorazepate, nitrazepam, clonazepam, lorazepam), acetylureas (e.g., phenacemide, pheneturide) and sulfonamides and carbonic anhydrase inhibitors (e.g., acetazolamide, sulthiame, bromide). ,), gabapetin, lamotrigine, primidone, and valproate or pro-drugs or metabolic precursors of any such anticonvulsant agents. Because of its method of administration, dosage and availability, phenytoin is described in detail below. That does not preclude the use of the other drugs in this invention. Furthermore, it is also known that the effectiveness of the anti-shivering drugs may be greatly enhanced by the application of a warming blanket at the times when the patient is at or below what would be the patient""s shivering threshold if the drugs had not been administered. Thus any of the methods described below may include the step of placing a warming blanket over the surface of the patient at the same time as administering the anti-shivering drugs.
In one embodiment of the invention, the aforementioned method is utilized to lower a patient""s body temperature below its set point temperature while reducing shivering.
In yet another embodiment of the invention, the aforementioned method is utilized to raise a patient""s body temperature from an initial temperature below the set point temperature while reducing shivering.
Another embodiment of this invention is to utilize the aforementioned method to raise a patient""s body temperature at a predetermined rate while reducing shivering.
Still another embodiment of the invention is to utilize the aforementioned method to slowly and controllably rewarm a hypothermic patient from a temperature below the set point temperature toward normothermia.
Another embodiment of the invention is to utilize the aforementioned method to maintain a patient""s body temperature at a stable temperature below the set point temperature while reducing shivering.
Yet another embodiment of the invention comprises controlling a patient""s body temperature by placing a heat exchange device having a heat exchange region into the vascular system of the patient and controlling the temperature of the heat exchange region for a sufficient time to affect the temperature of all or a portion of the patient""s body, while administering an agent selected from the group consisting of xcex12-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug to the patient.
Still another embodiment of the invention is a method of controlling a patient""s body temperature by administering an agent selected from the group consisting of xcex12-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug to the patient while using a heat exchange device that is a catheter and the heat exchange region comprises a balloon on the catheter, the temperature of the balloon being controlled by the circulation of a heat exchange fluid through the interior of the balloon. The catheter may have a shaft for the circulation of heat exchange fluid, where fluid circulates through the shaft and through the interior of the balloon.
Another embodiment of the invention relates to controlling the temperature of all or a portion of a patient""s body by using a heat exchange device in combination with an agent selected from the group consisting of xcex12-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug or pharmaceutically acceptable salt thereof.
Yet another embodiment of the invention is a method of controlling the temperature of a patient by using a heat exchange device and administering dexmedetomidine.
Yet another embodiment of the invention is a method of controlling the temperature of a patient by using a heat exchange device and administering nefopam.
Yet another embodiment of the invention is a method of controlling the temperature of a patient by using a heat exchange device and administering neurotensin.
In yet anther embodiment of the invention, a method is provided for controlling the temperature of a patient by using a heat exchange device and administering an anticonvulsant drug.
In yet anther embodiment of the invention, a method is provided for controlling the temperature of a patient by using a heat exchange device and administering an intravenous dose of fosphenytoin.
The present invention further comprises a method of controlling a patient""s body temperature below its set point temperature with an internal heat exchange device, while simultaneously inactivating the shivering response of the patient.
One embodiment of the invention pertains to a method of controlling the temperature of a patient below the set point temperature comprising the steps of: (a) employing internal in vivo core temperature regulation; and (b) administering an xcex12-adrenoreceptor agonist.
One embodiment of the invention pertains to a method of controlling the temperature of a patient below the set point temperature comprising the steps of: (a) employing internal in vivo core temperature regulation; and (b) administering of an anticonvulsant drug.
One embodiment of the invention pertains to a method of controlling the temperature of a patient below the set point temperature comprising the steps of: (a) employing internal in vivo core temperature regulation; (b) placing a warming blanket over the surface of the patient, and (c) administering an anticonvulsant drug.
In another embodiment of the invention, the step of employing internal in vivo core temperature regulation comprises placing a heat exchange device in the blood vessels of the patient, where the heat exchange device has a heat exchange region which is in contact with the flowing blood of the patient; and controlling the temperature of the heat exchange region for a sufficient time to affect the temperature of the patient, while administering an agent selected from the group consisting of xcex12-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug to the patient.
Yet another embodiment of the invention is a kit for reducing the temperature of a patient comprising a heat exchange device and an agent selected from the group consisting of xcex12-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors and neuropeptides. The kit may further comprising a set of instructions for use of the heat exchange device and/or administration of the agent. The kit may also comprise a control system which measures patient body temperature and controls the heat exchange device in response to the body temperature.
These and other embodiments of the invention are achieved by the method, apparatus, kit and composition described herein where a patient""s body temperature is lowered, such as by inducing hypothermia, utilizing a heat exchange device in combination with an agent selected from the group consisting of xcex12-adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug. Such device can comprise an elongate flexible catheter having a heat exchanger that operates to exchange heat between tissue, blood or other body fluid that flows in or is positioned in heat exchanging proximity thereto.
Further aspects and details of the present invention will become apparent to those of skill in the relevant art upon reading and understanding of the detailed description of preferred embodiments set forth here below. Each of the embodiments disclosed below may be considered individually or in combination with any of the other variations and aspects of the invention.